The discovery of a novel molecular switch that powerfully modulates nerve cell activity offers the potential for new mood disorder and epilepsy treatments, University of California, Irvine researchers report.

The researchers looked at the role of the natural substance cholecystokinin (CCK) in modulating communication between cells in the brain. CCK, originally isolated from the digestive tract, is one of the most abundant small proteins, or peptides, in the brain, and it is linked to psychiatric disorders such as anxiety, depression, and schizophrenia.

The study appears as an Advanced Online Publication in Nature Neuroscience.

Using sophisticated electrophysiological measurements, the UC Irvine team showed that CCK functions in the brain as an extremely specific switch with a highly unusual, dual action. On the one hand, CCK enhances the synthesis and release of natural marijuana-like (endocannabinoid) substances from a particular class of nerve cells known to modulate neuronal excitability in brain circuits critical for cognition and mood. On the other hand, CCK robustly increases electrical activity in a different class of nerve cells that play critical roles in learning and memory.

“These results reveal a new mechanism for CCK to regulate nerve cell activity in a highly specific manner,” said Csaba Foldy, postdoctoral researcher in anatomy and neurobiology and lead author of the study.

The study looked at the hippocampus, the region of the brain involved in learning, memory and emotion. Damage or alterations to the hippocampus can cause cognitive disorders, epilepsy, and mental illness.

“By linking CCK actions to endocannabinoids, the study provides novel possibilities for the future development of therapies for a number of neurological diseases,” said Ivan Soltesz, professor and chair of the Department of Anatomy and Neurobiology and senior author of the study. “Cannabinoid compounds are interesting because they act through special receptors on nerve cells to modulate these cells’ behavior.”

“This discovery offers the potential for new drug therapies because the link between CCK and cannabinoids can now be further investigated to determine how its modulation by either pharmacological or genetic means alters excitability in the hippocampus,” he added.

In addition to Foldy and Soltesz, UC Irvine graduate student Soo Yeun Lee and postdoctoral fellows Janos Szabadics and Axel Neu also participated in the research. This study was sponsored by the National Institute of Neurological Diseases and Stroke, the George E. Hewitt Foundation for Medical Research, and the Deutsche Forschungsgemeinschaft. Neu is currently at the University of Hamburg, Germany.